Synthesis of selenocysteine peptides and their oxidation to diselenide-bridged compounds

Besse, Dörthe; Moröder, Luis

doi:10.1002/(sici)1099-1387(199711)3:6<442::aid-psc122>3.0.co;2-2

Cited by 64 publications

(58 citation statements)

References 42 publications

(52 reference statements)

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“…General Strategy-The synthesis of selenocysteine-containing peptides has been limited due to the considerable chemical difficulties experienced by several laboratories (35). Most of the chemistry developed to date has employed the Fmoc-SPPS strategy and the Se-4-methoxybenzyl derivative.…”

Section: Resultsmentioning

confidence: 99%

α-Selenoconotoxins, a New Class of Potent α7 Neuronal Nicotinic Receptor Antagonists

Armishaw

Daly

Nevin

et al. 2006

Journal of Biological Chemistry

173

198

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]ImI) disulfide bonds with a diselenide bond. Each analogue demonstrated remarkable stability to reduction or scrambling under a range of chemical and biological reducing conditions. Three-dimensional structural characterization by NMR and CD spectroscopy indicates conformational preferences that are very similar to those of native ImI, suggesting fully isomorphic structures. Additionally, full bioactivity was retained at the ␣ 7 nicotinic acetylcholine receptor, with each selenoanalogue exhibiting a dose-response curve that overlaps with wild-type ImI, thus further supporting an isomorphic structure. These results demonstrate that selenoconotoxins can be used as highly stable scaffolds for the design of new drugs.

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Section: Resultsmentioning

confidence: 99%

α-Selenoconotoxins, a New Class of Potent α7 Neuronal Nicotinic Receptor Antagonists

Armishaw

Daly

Nevin

et al. 2006

Journal of Biological Chemistry

173

198

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Section: Synthesis Conditions For Peptides Containing Selenocysteinementioning

confidence: 99%

“…Besse and Moroder have diminished these problems by using the pentafluorophenyl esters of both Sec and Cys derivatives and eliminating the use of tertiary bases during the elongation step. Their optimized procedure also includes minimizing the time that the resin is exposed to piperidine in the deprotection step [49].A procedure that has worked well in my laboratory is a protocol developed by Barany who has long recognized that racemization for Cys derivatives is also a problem in solid-phase peptide synthesis [50]. This protocol eliminates any preactivation step and uses a weak base (collidine) in place of DIEA or NMM.…”

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confidence: 99%

Incorporation of Selenocysteine into Proteins Using Peptide Ligation

Hondal

2005

PPL

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Expressed protein ligation has become a frequently used technique to insert non-standard amino acids into proteins. The technique has been adapted to insert selenocysteine residues in place of cysteine residue in proteins, taking advantage of the similarity in the chemistries of sulfur and selenium. This replacement can confer unique structural and catalytic properties to enzymes and proteins. The development of this technique also allows for naturally occurring selenoproteins to be produced semisynthetically. KeywordsSelenocysteine; expressed protein ligation; thioredoxin reductase; semisynthetic Selenium, the mysterious moon-metalThe Swedish chemist, J.J. Berzilius discovered the 34 th element of the periodic table in 1817 and named it after the Greek goddess of the moon, Selene [1]. It is wholly appropriate that he named this element after the moon-goddess, because selenium, like the moon, has remained mysterious to science until the modern eraThe biological role of selenium began to be realized when Schwarz discovered a dietary factor that was necessary to prevent liver necrosis in rats [2]. He called this mysterious nutritional requirement, "Factor 3". He then determined that this dietary factor was the trace element selenium. In the 1970's, Chinese scientists reported that selenium could prevent a childhood cardiomyopathy known as Keshan disease [3], much like vitamin C can prevent the onset of scurvy. Beck and Levander later showed that both influenza and coxsackie viruses accumulate genetic mutations when these viruses have infected animal hosts that are deficient in selenium or vitamin E [4][5]. Keshan disease is caused when coxsackie virus mutates to a more virulent strain in a host deficient in selenium. In the 1980's, it was discovered that selenium is the only trace element that is incorporated directly into proteins as part of the polypeptide chain. [6]. The incorporation of selenium into proteins, known as selenoproteins, is beginning to explain the important role that selenium plays in human health. A number of important examples can be cited. Selenium is vital to the function of the thyroid gland. The key enzyme in the thyroid gland, which converts thyroxin (T4) to triidothyronine (T3), contains selenium [7]. Selenium is absolutely essential to human male fertility because an enzyme in the testes containing selenium protects developing sperm from oxidative injury [8]. There has long been anecdotal evidence that selenium offers † This work was supported by grant GM070742-01 NIH Public Access Selenium and the split personality of the genetic codeMany of the health benefits of selenium can be explained by its incorporation into proteins as the "21 st " amino acid, selenocysteine [12][13]. This amino acid, though rare, is ubiquitous in all of the kingdoms of life being found in eukarya, prokarya, and archea [14][15]. Examples of selenocysteine-containing proteins are found in plants, fungi, mammals, bacteria, and fish [16]. Like the other standard proteinogenic amino acids, selenocysteine i...

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“…Oxidative deprotection using I 2 and DMSO has also been used as a method to effect the removal of Bzl, Mob, and Acm groups [12][13][14][15]. In our experience, the use of I 2 is highly problematic as it is so reactive that reaction conditions must be optimized for each individual peptide.…”

Section: Introductionmentioning

confidence: 99%

“…Formation of dehydroalanine and iodinated adducts are common side reactions. Moreover, the target peptide will be oxidized to a disulfide or diselenide with the use of this reagent [13]. The use of DMSO as an oxidative deprotection reagent for the removal of Cys(Mob) groups, however, has met with some success [16].…”

Section: Introductionmentioning

confidence: 99%

Studies on deprotection of cysteine and selenocysteine side‐chain protecting groups

Harris¹,

Flemer²,

Hondal³

2006

Journal of Peptide Science

101

113

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Abstract:We present here a simple method for deprotecting p-methoxybenzyl groups and acetamidomethyl groups from the sidechains of cysteine and selenocysteine. This method uses the highly elecrophilic, aromatic disulfides 2,2 -dithiobis(5-nitropyridine) (DTNP) and 2,2 -dithiodipyridine (DTP) dissolved in TFA to effect removal of these heretofore difficult-to-remove protecting groups. The dissolution of these reagents in TFA, in fact, serves to 'activate' them for the deprotection reaction because protonation of the nitrogen atom of the pyridine ring makes the disulfide bond more electrophilic. Thus, these reagents can be added to any standard cleavage cocktail used in peptide synthesis.The p-methoxybenzyl group of selenocysteine is easily removed by DTNP. Only sub-stoichiometric amounts of DTNP are required to cause full removal of the p-methoxybenzyl group, with as little as 0.2 equivalents necessary to effect 70% removal of the protecting group. In order to remove the p-methoxybenzyl group from cysteine, 2 equivalents of DTNP and the addition of thioanisole was required to effect removal. Thioanisole was absolutely required for the reaction in the case of the sulfur-containing amino acids, while it was not required for selenocysteine. The results were consistent with thioanisole acting as a catalyst. The acetamidomethyl group of cysteine could also be removed using DTNP, but required the addition of >15 equivalents to be effective. DTP was less robust as a deprotection reagent. We also demonstrate that this chemistry can be used in a simultaneous cyclization/deprotection reaction between selenocysteine and cysteine residues protected by p-methoxybenzyl groups to form a selenylsulfide bond, demonstrating future high utility of the deprotection method.

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Synthesis of selenocysteine peptides and their oxidation to diselenide-bridged compounds

Cited by 64 publications

References 42 publications

α-Selenoconotoxins, a New Class of Potent α7 Neuronal Nicotinic Receptor Antagonists

α-Selenoconotoxins, a New Class of Potent α7 Neuronal Nicotinic Receptor Antagonists

Incorporation of Selenocysteine into Proteins Using Peptide Ligation

Studies on deprotection of cysteine and selenocysteine side‐chain protecting groups

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